Schizophrenia is a debilitating disorder which affects 1% of the population at a substantial cost to the individual, their family and society. Cognitive ability is the best predictor of employment, social integration and relapse in schizophrenia, but current pharmacotherapies do not address cognitive dysfunction. A core component of cognition is working memory (WM), which depends upon proper activation of dorsolateral prefrontal cortex (DLPFC) circuitry, and both WM and DLPFC activation are impaired in schizophrenia. To identify therapeutic targets for improving WM, the underlying nature of DLPFC circuitry abnormalities must be identified. Parvalbumin (PV) basket cells synapse onto the perisomatic region of pyramidal cells and are critical for synchronizing neural populations to oscillate in the gamma range (30-90 Hz). Gamma oscillations are thought to underlie WM ability, and schizophrenia patient show impaired gamma oscillations during WM tasks. Recent evidence demonstrates that PV basket cell axonal arbors and synapses are significantly diminished if adequate levels of GAD67 are not available during development In schizophrenia DLPFC, GAD67 mRNA is undetectable in 45% of PV interneurons, suggesting these GAD67-negative, PV-positive interneurons form fewer connections with pyramidal cells. Thus, alterations in PV basket cell connections may contribute to the circuitry abnormalities underlying impaired WM in schizophrenia. To test the hypothesis that PV basket cell inputs are diminished in schizophrenia, pre- and postsynaptic markers are examined in DLPFC tissue from schizophrenia relative to comparison subjects. In Aim 1, a novel confocal microscopic method is used to test the hypothesis that DLPFC pyramidal somata receives fewer PV basket cell inputs in schizophrenia. PV basket cells synapsing onto pyramidal somata signal via GABAa receptors containing alpha subunits. Thus, in Aim 2, the same method is used to test the hypothesis that the number of alpha subunit clusters on pyramidal somal membranes is lower in schizophrenia. Recent evidence indicates that PV basket cell inputs onto pyramidal cells, but not interneurons, are important for gamma ocsillations. Thus, in Aim 3 the hypothesis that alpha subunits are exclusively lower in pyramidal cells is tested using dual-label in situ hybridization to determine the percentage of pyramidal cells and interneuons containing alpha mRNA in schizophrenia. Relevance: Schizophrenia affects over 3 million Americans at a cost of $62 billion a year, and cognitive ability is the best predictor of employment and relpase in these patients. No treatments which improve cognition in schizophrenia are currently available. The proposed project examines circuitry abnormalities which likely contribute to cognitive impairment in schizophrenia.